Project Summary: Owing to the continual growth of the aged population and the constant threat of newly emerging infectious disease, it is critical that we understand the ability of the elderly to respond to new infections. It is well accepted that immune function declines with aging. Consequently, the elderly are at an increased risk for morbidity and mortality associated with infectious disease. It has been speculated that age-related reductions in the size of naive T cell peripheral pool, presumably due to decreases in thymic output and the expansion of CD44high activated/memory T cells, may result in contraction of the T cell repertoire and a lack of responsiveness to new infections. To test this hypothesis, the first part of the research proposal will analyze the repertoire of virus-specific CD8 T cells elicited in individual aged mice after primary influenza virus infection (in terms of specificity and effector function) and assess the impact of repertoire on the efficacy of viral clearance. Evidence supporting an association between age-related changes in T cell repertoire diversity and defective anti-viral immune responses would greatly influence methodologies of improving vaccination in the elderly. There is an age-related decline in the naive T cell population, with activated/memory (CD44high) T cells dominating the peripheral CD8 T cell repertoire in aged mice. Following, the second part of the research proposal will use adoptive transfer approaches to define the relative contributions of naive and potentially cross-reactive memory CD8 T cells to the immune response against influenza in aged mice. Knowledge concerning the potential of aged naive and/or heterologous memory CD8 T cells to respond to a primary viral infection is critical for the development of vaccines or therapies aimed at reducing the risks of morbidity and mortality associated with viral infections in elderly populations. Relevance: Immune function declines with increasing age. As such, the elderly are at an increased risk for infectious disease, particularly those caused by newly emerging viruses (SARS) or new strains of known viruses (H5N1 avian influenza). Results from these studies will have important implications for the development of vaccines or therapeutics aimed at reducing the incidence of respiratory viruses in the elderly. [unreadable] [unreadable] [unreadable]